Preparation Of Surface Imprinted Material Of Chiral Drug And Study On Its Recognition And Resolution Properties

It has become an important direction of development in the filed of global science in medicine to obtain high efficacy of optically pure chiral drugs. There are many difficulties to synthesize optically pure chiral drugs by synthesis of chiral source and chiral asymmetric synthesis, so resolving a racemate effectively has become the most effective way to obtain optically pure chiral drugs.In this study, surface imprinted materials of R-mandelic acid and S-ibuprofen with high performance were prepared with a new surface imprinting technique of “synchronously graft-polymerizing and molecule imprinting” in non-aqueous media, and their chiral recognition and resolution properties were studied and valuable findings were obtained.First, micron-sized silicon particles were chemically surface-modified with coupling agent γ-mercaptopropyl trimethoxysilane(MPMS) and modified particles MPMS/SiO2 containing a mercapto group was prepared; a redox surface-initiating system was made up by the benzoyl peroxide(BPO) in the solution and the mercapto groups on the surface of modified particles, and the graft-polymerization of 2-hydroethyl methylacrylate(HEMA)was achieved and the grafted particles PHEMA/SiO2 were successfully prepared; the grafted particles were characterized with FTIR, TGA and SEM; the effects of the main factors on the graft polymerization of HEMA were examined. The results showed that-SH/BPO was an effective surface of the initiating system and it could be successfully initiated in the monomer HEMA grafted silica particle surface polymerization. In the graft polymerization process, the grafting degree of PHEMA could get up to 24.9 g/100 g at suitable reaction conditions: the consistence of HEMA was 7.0%, the used amount of initiator was 1.0%, temperature was 65℃and time was 16 h.Secondly, the adsorption behavior of the graft particles PHEMA/SiO2 towards mandelic acid and ibuprofen were examined, and the adsorption mechanism was mainly studied. The experimental results showd that the ester carbonyl oxygen atom and alcohol hydroxyl of the graft particles PHEMA/SiO2 could produce ordinary bonds and π-hydrogen bonding interaction, and the graft particles PHEMA/Si O2 had strong adsorption ability for mandelic acid and ibuprofen molecule by right of the multi-site hydrogen bonds. Adsorption of PHEMA/SiO2 in the non-polar solvent was stronger than adsorption in the polar solvent. At 25℃, the adsorption capacity of graft microparticles PHEMA/SiO2 for mandelic acid was 245.8 mg/g and 216.6 mg/g respectively in dichloroethane(DCE) and N,Ndimethylformamide(DMF); the adsorption capacity of graft particulate PHEMA/SiO2 for ibuprofen was 156.5 mg/g in DCE. Since the hydrogen bonds are highly sensitive to temperature, as the temperature increases, the adsorption capacity decreases.In non-aqueous media, the graft polymer PHEMA showd strong hydrogen bonding interactions for mandelic acid molecules and ibuprofen molecules, so it was obvious that strong hydrogen bonding interactions also existed between the monomer and mandel ic acid molecule or ibuprofen molecular. Based on this, in this study, R-mandelic acid molecule surface imprinted material MIP-PHEMA/SiO2 were prepared with HEMA as functional monomer in a non-aqueous medium. The surface imprinted of mandelic acid molecule was performed successfully under the-SH/BPO surface initiator system with R-mandelic acid as the template molecule and N,N’-methylene-bis-acrylamide(MBA) as linking agent by the novel surface imprinting technique of synchronously graft-polymerizing and molecule imprinting established by our research group; both static and dynamic methods were adopted to study the binding performance and identifying characteristics for R-mandelic acid and their chiral resolution performance were also examined. The results showd that, R-mandelic surface imprinted material MIP-PHEMA/SiO2 for isomer R-mandelic acid had a specific identification and resolution performance: with respect to S-mandelic acid, the selectivity coefficient of MIP-PHEMA/SiO2 for R-mandelic acid was 5.02; the optical purity of supernatant after adsorption containing mainly S-mandelic was 44%; the optical purity of eluent containing mainly R-mandelic acid was up to 85%. In addition, the amount of the crosslinking agent and template molecule also had some influence on the selectivity coefficient of imprinted materials: suitable crosslinking agents MBA consumption was 1/4 of the amount of substance of HEMA; suitable amount of R- mandelic acid was 1/3 of the amount of substance of HEMA.Finally, the surface imprinted of ibuprofen molecule was performed successfully under the-SH/BPO surface initiator system with S-ibuprofen as the template molecule, HEMA as functional monomer and ethylene glycol methacrylate(EGDMA) as crosslinking agent in a non-aqueous medium, and then S-ibuprofen molecule surface imprinted materials MIP-PHEMA/SiO2 were prepared successfully; both static and dynamic methods were adopted to study the binding performance and identifying characteristics for S-ibuprofen and their chiral resolution performance were also examined. The results showd that, S-ibuprofen surface imprinted material MIP-PHEMA/Si O2 for isomer S-ibuprofen had a specific identification and resolution performance: with respect to R-ibuprofen, the selectivity coefficient of MIPPHEMA/SiO2 for S-ibuprofen was 4.99; the optical purity of supernatant after adsorption containing mainly R-ibuprofen was 44%; the optical purity of eluent containing mainly Sibuprofen was up to 79%. In addition, the amount of the crosslinking agent and template molecule also had some influence on the selectivity coefficient of imprinted materials: suitable crosslinking agents EGDMA consumption was 1/4 of the amount of substance of HEMA; suitable amount of S-ibuprofen was 1/5 of the amount of substance of HEMA.